Oxaliplatin induces immunogenic cell death in hepatocellular carcinoma cells and synergizes with immune checkpoint blockade therapy

2020 ◽  
Vol 43 (6) ◽  
pp. 1203-1214 ◽  
Author(s):  
Hanzhang Zhu ◽  
Yuqiang Shan ◽  
Ke Ge ◽  
Jun Lu ◽  
Wencheng Kong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Carcinoma Cells ◽  
Checkpoint Blockade ◽  
Immunogenic Cell Death ◽  
Hepatocellular Carcinoma Cells

scholarly journals The Role of Immune Checkpoint Blockade in the Hepatocellular Carcinoma: A Review of Clinical Trials

2021 ◽  
Vol 11 ◽  
Author(s):  
Muhammet Ozer ◽  
Andrew George ◽  
Suleyman Yasin Goksu ◽  
Thomas J. George ◽  
Ilyas Sahin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Cell Death ◽  
Liver Cancer ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Primary Liver Cancer ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Line Treatment

The prevalence of primary liver cancer is rapidly rising all around the world. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Unfortunately, the traditional treatment methods to cure HCC showed poor efficacy in patients who are not candidates for liver transplantation. Until recently, tyrosine kinase inhibitors (TKIs) were the front-line treatment for unresectable liver cancer. However, rapidly emerging new data has drastically changed the landscape of HCC treatment. The combination treatment of atezolizumab plus bevacizumab (immunotherapy plus anti-VEGF) was shown to provide superior outcomes and has become the new standard first-line treatment for unresectable or metastatic HCC. Currently, ongoing clinical trials with immune checkpoint blockade (ICB) have focused on assessing the benefit of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) as monotherapies or combination therapies in patients with HCC. In this review, we briefly discuss the mechanisms underlying various novel immune checkpoint blockade therapies and combination modalities along with recent/ongoing clinical trials which may generate innovative new treatment approaches with potential new FDA approvals for HCC treatment in the near future.

scholarly journals Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000282 ◽  
Author(s):  
Lihong Wang-Bishop ◽  
Mohamed Wehbe ◽  
Daniel Shae ◽  
Jamaal James ◽  
Benjamin C. Hacker ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immunogenic Cell Death ◽  
Intratumoral Administration ◽  
Cytosolic Delivery ◽  
Sting Pathway

BackgroundNeuroblastoma (NB) is a childhood cancer for which new treatment options are needed. The success of immune checkpoint blockade in the treatment of adult solid tumors has prompted the exploration of immunotherapy in NB; however, clinical evidence indicates that the vast majority of NB patients do not respond to single-agent checkpoint inhibitors. This motivates a need for therapeutic strategies to increase NB tumor immunogenicity. The goal of this study was to evaluate a new immunotherapeutic strategy for NB based on potent activation of the stimulator of interferon genes (STING) pathway.MethodsTo promote STING activation in NB cells and tumors, we utilized STING-activating nanoparticles (STING-NPs) that are designed to mediate efficient cytosolic delivery of the endogenous STING ligand, 2’3’-cGAMP. We investigated tumor-intrinsic responses to STING activation in both MYCN-amplified and non-amplified NB cell lines, evaluating effects on STING signaling, apoptosis, and the induction of immunogenic cell death. The effects of intratumoral administration of STING-NPs on CD8+T cell infiltration, tumor growth, and response to response to PD-L1 checkpoint blockade were evaluated in syngeneic models of MYCN-amplified and non-amplified NB.ResultsThe efficient cytosolic delivery of 2’3’-cGAMP enabled by STING-NPs triggered tumor-intrinsic STING signaling effects in both MYCN-amplified and non-amplified NB cell lines, resulting in increased expression of interferon-stimulated genes and pro-inflammatory cytokines as well as NB cell death at concentrations 2000-fold to 10000-fold lower than free 2’3’-cGAMP. STING-mediated cell death in NB was associated with release or expression of several danger associated molecular patterns that are hallmarks of immunogenic cell death, which was further validated via cell-based vaccination and tumor challenge studies. Intratumoral administration of STING-NPs enhanced STING activation relative to free 2’3’-cGAMP in NB tumor models, converting poorly immunogenic tumors into tumoricidal and T cell-inflamed microenvironments and resulting in inhibition of tumor growth, increased survival, and induction of immunological memory that protected against tumor re-challenge. In a model of MYCN-amplified NB, STING-NPs generated an abscopal response that inhibited distal tumor growth and improved response to PD-L1 immune checkpoint blockade.ConclusionsWe have demonstrated that activation of the STING pathway, here enabled by a nanomedicine approach, stimulates immunogenic cell death and remodels the tumor immune microenvironment to inhibit NB tumor growth and improve responses to immune checkpoint blockade, providing a multifaceted immunotherapeutic approach with potential to enhance immunotherapy outcomes in NB.

scholarly journals Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

2019 ◽  
Author(s):  
Sarah Nersesian ◽  
Noor Shakfa ◽  
Nichole Peterson ◽  
Thiago Vidotto ◽  
Afrakoma AfriyieAsante ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Death ◽  
Clinical Study ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Serous Carcinoma ◽  
Immunogenic Cell Death ◽  
Pathway Activation ◽  
Sting Pathway

AbstractPoor response to platinum/taxane-based chemotherapy has remained a major hurdle in the management of high grade serous carcinoma of the ovary (HGSC). Recurrent HGSC is often treated with liposomal doxorubicin as a second line chemotherapy. Unfortunately, HGSC patients have not benefited from immunotherapies targeting the PD-1/PD-L1 immune checkpoint axis. In a pre-clinical study evaluating the efficacy of a “Stimulator of Interferon Genes” (STING) agonist, we demonstrated the synergistic potential of STING pathway activation in enhancing response to carboplatin chemotherapy and sensitization to PD-1 immune checkpoint blockade (ICB). Since carboplatin and doxorubicin exhibit distinct immunogenic cell death (ICD) inducing potential, we investigated the chemotherapy specific effect in the magnitude of response to exogenous STING pathway activation. Immunocompetent C57/BL6 mice were implanted with ID8-Trp53−/− cells followed by treatment with carboplatin or doxorubicin. Towards rationalized addition of STING agonist with or without PD-L1 blockade, we first determined the expression of 60 known ICD associated genes at an early time point following the initial treatment with carboplatin or doxorubicin with or without STING agonist. Doxorubicin treated tumours showed significantly higher expression of ICD genes, Cxcl10, Cd274, Isg15, Psmb9 and Calr. Expression changes were further amplified following the addition of STING agonist. Significantly higher expression of Cxcl10 and Isg15 were observed in the doxorubicin + STING agonist treated mice compared to carboplatin + STING agonist combination. Interestingly, Ccl5 gene expression was higher in the tumours from carboplatin or carboplatin and STING agonist combination treated mice compared to those treated with doxorubicin. Plasma cytokine analysis showed distinct profiles of CXCL10, CCL5, MCP-1 and IL6 post treatment with each chemotherapy type. Doxorubicin monotherapy treated mice showed significantly longer overall survival compared to their carboplatin counterparts with further increases following addition of either STING agonist or PD-L1 ICB. However, despite the stronger ICD inducing ability of doxorubicin, overall survival of mice treated with carboplatin + STING agonist + PD-L1 ICB was the longest. Findings from our pre-clinical study provide novel insights for rationalized combinations of immune sensitizing agents such as STING pathway activators to improve response of HGSC patients to chemotherapy and ICB in the primary and recurrent settings.

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